Cephalosporins bearing a 3-exomethylene group are valuable intermediates in the synthesis of cephalosporins having antibacterial activity. Chauvette, for example, in U.S. Pat. No. 3,925,372, described the ozonolysis of 3-exomethylenecephams to 3-hydroxy-3-cephems, followed by halogenation of the latter compounds to give 3-halo-3-cephem antibiotics. One 3-chloro-3-cephem is now known commercially as cefaclor.
Several processes are known for the synthesis of 3-exomethylenecephams. Chauvette and Pennington, in J. Org. Chem., 38, 2994 (1973), disclose the reaction of a 3-acetoxy-3-cephem (a cephalosporanic acid derivative) with a sulfur nucleophile such as thiourea to give a 3-thiomethyl-3-cephem derivative, and then reduction of the latter compound with zinc in formic acid and dimethylformamide to give the corresponding 3-exomethylenecepham. Ochiai et al., in U.S. Pat. No. 3,792,995, report an electrolytic reductive cleavage of the 3-acetoxy group of cephalosporanic acid derivatives to give 3-exomethylenecephams. Teijin, in Japanese Pat. No. 51,141889, discloses the preparation of 3-exomethylenecephams from 3-trifluoroacetoxy-3-methylcephams by reaction with a strong acid such as methanesulfonic acid. Kukolja, in U.S. Pat. No. 4,052,387, described the conversion of monocyclic azetidinone-2-sulfinyl chlorides to 3-exomethylenecephams by reaction with a Friedel-Crafts catalyst. Ponticello et al., in U.S. Pat. No. 3,883,518, disclose the reduction with zinc and acetic acid of a 3-carbamoyloxymethyl or 3-acetoxymethyl cephalosporin to give the corresponding 3-exomethylenecepham.
All of the prior art methods for preparing 3-exomethylenecephams suffer in several respects. Those methods that require C.sup.3 -derivatives other than acetoxy are costly in that additional reaction steps from natural products are required. The methods that require the presence of acids for prolonged periods of time suffer from .DELTA..sup.3 isomerization. Moreover, yields of 3-exomethylenecephams from prior art processes generally have been low.
An object of this invention is to provide an improved process for preparing 3-exomethylenecephams from 3-acetoxymethyl-3-cephems. The method of this invention differs from the prior art processes in that high yields of 3-exomethylenecephams are realized, and no free acid is permitted in the reaction mixture, thus obviating the risk of substantial undesired side reactions.